Claims for Patent: 8,642,582

Summary for Patent: 8,642,582

Title:	Morpholinone compounds as factor IXa inhibitors
Abstract:	The present invention provides a compound of Formula (I) ##STR00001## as described herein, or a pharmaceutically acceptable salt or a solvate thereof. The present invention also provides pharmaceutical compositions comprising one or more said compounds, and methods for using said compounds for treating or preventing a thromboses, embolisms, hypercoagulability or fibrotic changes.
Inventor(s):	Nishida; Hidemitsu (Tokyo, JP), Saitoh; Fumihiko (Tokyo, JP), Hirabayashi; Tomokazu (Tokyo, JP), Chackalamannil; Samuel (Califon, NJ), Chan; Tin-Yau (Edison, NJ), Chelliah; Mariappan V. (Edison, NJ), Clasby; Martin C. (Plainsboro, NJ), Dwyer; Michael (Scotch Plains, NJ), Greenlee; William J. (Teaneck, NJ), Xia; Yan (Edison, NJ)
Assignee:	Merck Sharp & Dohme Corp. (Rahway, NJ)
Application Number:	12/744,736
Patent Claims:	1. A compound of the Formula (I) ##STR00381## or a pharmaceutically acceptable salt thereof; wherein: R1 is selected from the group consisting of: 1) --(C.sub.6-C.sub.14)-aryl, which is unsubstituted or substituted independently with one to four Y; 2) -(three- to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y; 3) --(C.sub.6-C.sub.14)-aryl-U--(C.sub.6-C.sub.14)-aryl, wherein each of said --(C.sub.6-C.sub.14)-aryl- independently is unsubstituted or substituted independently with one to four Y; 4) --(C.sub.6-C.sub.14)-aryl-U--(C.sub.3-C.sub.12)-cycloalkyl, wherein said --(C.sub.6-C.sub.14)-aryl and --(C.sub.3-C.sub.12)-cycloalkyl independently are unsubstituted or substituted independently with one to four Y; 5) --(C.sub.6-C.sub.14)-aryl-U-(three- to fifteen-membered heterocyclic ring), wherein said --(C.sub.6-C.sub.14)-aryl and said (three- to fifteen-membered heterocyclic ring) are independently unsubstituted or substituted independently with one to four Y; 6) --(three- to fifteen-membered heterocyclic ring)-U-(C.sub.6-C.sub.14)-aryl, wherein said --(C.sub.6-C.sub.14)-aryl and said (three- to fifteen-membered heterocyclic ring) are independently unsubstituted or substituted independently with one to four Y; 7) --(three- to fifteen-membered heterocyclic ring)-U-(three- to fifteen-membered heterocyclic ring), wherein each of said -(three- to fifteen-membered heterocyclic ring)- is independently unsubstituted or substituted independently with one to four Y; 8) --(three- to fifteen-membered heterocyclic ring)-U-(C.sub.3-C.sub.12)-cycloalkyl, wherein said --(C.sub.3-C.sub.12)-cycloalkyl, and said -(three- to fifteen-membered heterocyclic ring)- are independently unsubstituted or substituted independently with one to four Y; 9) --V--(C.sub.6-C.sub.14)-aryl, which is unsubstituted or substituted independently with one to four Y; and 10) --V-(three- to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y; R2 is selected from the group consisting of hydrogen atom, R3 is absent, or selected from the group consisting of hydrogen atom R4 is selected from the group consisting of: 1) --(C.sub.6-C.sub.14)-aryl-Z, wherein said Z is a basic nitrogen-containing group and wherein said --(C.sub.6-C.sub.14)-aryl is unsubstituted or substituted independently with one to four Y; 2) --(C.sub.3-C.sub.12)-cycloalkyl-Z, wherein said Z is a basic nitrogen-containing group and wherein said --(C.sub.3-C.sub.12)-cycloalkyl is unsubstituted or substituted independently with one to four Y; 3) --(three- to fifteen-membered heterocyclic ring)-Z, wherein said Z is a basic nitrogen-containing group and wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or additionally substituted independently with one to four Y; 4) --(three- to fifteen-membered heterocyclic ring)-U-(three- to fifteen-membered heterocyclic ring) -Z, wherein said Z is a basic nitrogen-containing group and wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or additionally substituted independently with one to four Y; 5) --(C.sub.6-C.sub.14)-aryl, which is unsubstituted or substituted independently with one to four Y; 6) --(C.sub.3-C.sub.12)-cycloalkyl, which is unsubstituted or substituted independently with one to four Y; 7) --(three- to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y; 8) -(three- to fifteen-membered heterocyclic ring)-U-(three- to fifteen-membered heterocyclic ring), wherein each of said (three- to fifteen-membered heterocyclic ring) is independently unsubstituted or substituted independently with one to four Y; each V independently is selected from the group consisting of --SO.sub.2--, --C(O)--, --C(O)--NH-- and --SO.sub.2--NH--, wherein the carbon atom of said --C(O)--NH-- or the sulfur atom of said --SO.sub.2--NH-- is connected to a nitrogen atom of the morpholinone ring, and wherein said --(C.sub.1-C.sub.4)-alkylene is unsubstituted or substituted independently with one to four T, or wherein geminal hydrogens in said --(C.sub.1-C.sub.4)-alkylene can be replaced by a (C.sub.3-C.sub.8)-cycloalkyl to form a spiro cyclic ring; each T independently is selected from the group consisting of: 1) halogen; 2) --(C.sub.1-C.sub.6)-alkyl, which is unsubstituted or substituted independently with one to four substituents selected from the group consisting of OH, --O--(C.sub.1-C.sub.4)-alkyl, --(C.sub.1-C.sub.3)-haloalkyl, --O--(C.sub.1-C.sub.3)-haloalkyl, --N--C(O)--OH and --N--C(O)--C.sub.1-C.sub.4)-alkyl; 3) --(C.sub.1-C.sub.3)-haloalkyl; 4) --(C.sub.3-C.sub.8)-cycloalkyl; 5) --OH; 6) --O--(C.sub.1-C.sub.4)-alkyl, which is unsubstituted or mono substituted with OH, --O--(C.sub.1-C.sub.4)-alkyl, --(C.sub.1-C.sub.3)-haloalkyl, --O--(C.sub.1-C.sub.3)-haloalkyl, --N--C(O)--OH or --N--C(O)--(C.sub.1-C.sub.4)-alkyl; 7) --O--(C.sub.1-C.sub.3)-haloalkyl; 8) --NO.sub.2; 9) --CN; 10) --N(R7)(R8); 11) --C(O)--N(R7)(R8); 12) --N(R8)-C(O)--R7; 13) --N(R8)-SO.sub.2--R7; 14) --SO.sub.2--(C.sub.1-C.sub.4)-alkyl; 15) --SO.sub.2--N(R7)(R8); 16) --SO.sub.2--(C.sub.1-C.sub.3)-haloalkyl; 17) --S--(C.sub.1-C.sub.4)-alkyl; 18) --S--(C.sub.1-C.sub.3)-haloalkyl; 19) --(C.sub.1-C.sub.6)-alkyl-N(R7)(R8); 20) --NH--C(O)--N(R7)(R8); 21) .dbd.O (oxo); and 22) --C(O)OR7; 23) --C(O)OR7; 24) --N--C(O)--OR7 wherein each of R7 and R8 independently is selected from the group consisting of a hydrogen atom, --(C.sub.3-C.sub.8)-cycloalkyl, halogen and --(C.sub.1-C.sub.6)-alkyl, wherein said --(C.sub.1-C.sub.6)-alkyl is optionally substituted with at least one substituent selected from the group consisting of OH, --O--(C.sub.1-C.sub.4)-alkyl, --(C.sub.1-C.sub.3)-fluoroalky, and --O--(C.sub.1-C.sub.3)-haloalkyl; W is selected from the group consisting of oxygen atom, X is selected from the group consisting of nitrogen atom Y is selected from the group consisting of: 1) halogen; 2) --(C.sub.1-C.sub.6)-alkyl; 3) --(C.sub.1-C.sub.3)-haloalkyl; 4) --(C.sub.3-C.sub.8)-cycloalkyl; 5) --OH; 6) --O--(C.sub.1-C.sub.3)-haloalkyl; 7) --NO.sub.2; 8) --CN; 9) --N(R7)(R8); 10) --C(O)--N(R7)(R8); 11) --N(R8)-C(O)--R7; 12) --N(R8)-SO.sub.2--R7; 13) --SO.sub.2--(C.sub.1-C.sub.4)-alkyl; 14) --SO.sub.2--N(R7)(R8); 15) --SO.sub.2--(C.sub.1-C.sub.3)-haloalkyl; 16) --S--(C.sub.1-C.sub.4)-alkyl; 17) --S--(C.sub.1-C.sub.3)-haloalkyl; 18) --(C.sub.1-C.sub.6)-alkyl-N(R7)(R8); 19) --N(R8) --C(O)--N(R7)(R8); 20) .dbd.O (oxo); 21) --SF.sub.5; 22) --C(O)OR7; 23) --N--C(O)--OR7 24) --N(R8)--C(O)--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl-(C.sub.- 6-C.sub.14)-aryl, wherein said --(C.sub.6-C.sub.14)-aryl is unsubstituted or substituted independently with one to four Y selected from (1) to (24) as set forth above; 25) --N(R8)--C(O)--(C.sub.1-C.sub.4)-alkyl-O--(C.sub.1-C.sub.4)-alkyl-(three- to fifteen-membered heterocyclic ring), wherein said -(three- to fifteen-membered heterocyclic ring) is unsubstituted or substituted independently with one to four Y selected from (1) to (24) as set forth above; wherein said --(C.sub.1-C.sub.4)-alkyl part or --(C.sub.1-C.sub.6)-alkyl part of 2), 6), 13), 16), 18), 24) or 25) of said Y is unsubstituted or substituted independently with one to four T; wherein each of R7 and R8 of 9), 10), 11), 12), 14), 18), 19), 22), 23), 24) or 25) of said Y independently is selected from the group consisting of hydrogen atom, --(C.sub.3-C.sub.8)-cycloalkyl, and --(C.sub.1-C.sub.6)-alkyl, wherein said --(C.sub.1-C.sub.6)-alkyl is optionally substituted with OH, --O--(C.sub.1-C.sub.4)-alkyl, --(C.sub.1-C.sub.3)-fluoroalkyl, --O--(C.sub.1-C.sub.3)-haloalkyl, --C(O)OH, or C(O)O--(C.sub.1-C.sub.6)alkyl; the dotted linkage between W and R4 of the substructure (III) ##STR00382## in Formula (I) is 1) absent. 2. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein substructure (III) ##STR00383## in Formula (I) is ##STR00384## 3. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein: R1 is selected from the group consisting of: 1) --(C.sub.6-C.sub.14)-aryl, which is unsubstituted or substituted independently with one to four Y; 2) -(three- to fifteen-membered heterocyclic ring), which is unsubstituted or substituted independently with one to four Y; 3) --(C.sub.6-C.sub.14)-aryl-U--(C.sub.6-C.sub.14)-aryl, wherein each of said --(C.sub.6-C.sub.14)-aryl independently is unsubstituted or substituted independently with one to four Y; 5) --(C.sub.6-C.sub.14)-aryl-U-(three- to fifteen-membered heterocyclic ring), in which said --(C.sub.6-C.sub.14)-aryl and said (three- to fifteen-membered heterocyclic ring) are independently unsubstituted or substituted independently with one to four Y; and 9)-V--(C.sub.6-C.sub.14)-aryl, wherein said --V--(C.sub.6-C.sub.14)-aryl is unsubstituted or substituted independently with one to four Y. 4. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is (C.sub.6-C.sub.14)-aryl, which is unsubstituted or substituted independently with one to four Y. 5. A compound of claim 1 or a pharmaceutically acceptable salt thereof wherein R1 is a phenyl group, which is unsubstituted or substituted independently with one to four Y. 6. A compound of claim 1 wherein said three- to fifteen-membered heterocyclic ring of R1 is represented by the Formula (a) ##STR00385## wherein Formula (a) is unsubstituted or substituted independently with one to four Y; and wherein: o and p are independently selected from 0 or 1; J, K, L and M are independently selected from the group consisting of CH.sub.2, C(O), NH, O and S(O)q, wherein q is 0, 1 or 2; D, E and F are independently selected from the group consisting of carbon atom, nitrogen atom, oxygen atom and sulfur atom. 7. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Z represents a radical selected from the group consisting of amino, imino, aminomethyl, amidino (carbamimidoyl), guanidino, azetidinyl, pyrrolidinyl, piperidinyl, pyridinyl and aminopyridinyl, and wherein any nitrogen atom of each of said aforementioned Z radicals is unsubstituted or substituted independently with one or two (C.sub.1-C.sub.6) alkyl. 8. A compound of claim 1 wherein R4 is a (three- to fifteen-membered heterocyclic ring)-Z, wherein said Z is a basic nitrogen-containing group and wherein said (three- to fifteen-membered heterocyclic ring) is unsubstituted or additionally substituted independently with one to four Y. 9. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is --(C.sub.6-C.sub.14)-aryl-Z, wherein Z is a basic nitrogen-containing group and wherein said --(C.sub.6-C.sub.14)-aryl is unsubstituted or additionally substituted independently with one to four Y. 10. A compound of claim 1 wherein R4 is -benzimidazole-Z, wherein Z is a basic nitrogen-containing group and wherein said benzimidazole is unsubstituted or additionally substituted independently with one to four Y. 11. A compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R4 is -phenyl-Z, wherein Z is a basic nitrogen-containing group and wherein said phenyl is unsubstituted or additionally substituted independently with one to four Y. 12. A compound of formula (I) of claim 1 consisting of: ##STR00386## or a pharmaceutically acceptable salt thereof, wherein R.sub.1 is a group selected from the group consisting of: ##STR00387## ##STR00388## ##STR00389## ##STR00390## ##STR00391## ##STR00392## ##STR00393## ##STR00394## ##STR00395## ##STR00396## ##STR00397## ##STR00398## ##STR00399## ##STR00400## ##STR00401## ##STR00402## ##STR00403## ##STR00404## ##STR00405## ##STR00406## ##STR00407## ##STR00408## and wherein ##STR00409## is selected from the group consisting of ##STR00410## ##STR00411## ##STR00412## ##STR00413## ##STR00414## ##STR00415## 13. A compound of formula (I) of claim 1 consisting of: N-(1-aminoisoquinolin-6-yl)-2-hydroxy-2-(3-oxo-4-p-tolylmorpholin-2-yl)-a- cetamide; N-(4-amidinophenyl)-2-hydroxy-2-(3-oxo-4-p-tolylmorpholin-2-yl)a- cetamide; 2-hydroxy-N-(1H-indol-5-yl)-2-(3-oxo-4-p-tolylmorpholin-2-yl)ace- tamide; 2-hydroxy-N-(2-methyl-1H-indol-5-yl)-2-(3-oxo-4-p-tolylmorpholin-2- -yl)-acetamide; N-[4-(aminomethyl)phenyl]-2-hydroxy-2-(3-oxo-4-p-tolylmorpholin-2-yl-acet- amide; N-(2-amino-3H-benzimidazol-5-yl)-2-hydroxy-2-(3-oxo-4-p-tolylmorpho- lin-2-yl)-acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-p-tolylmorpholin-2-yl- ]-acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(2,4-dimethylphenyl)-3-oxomorpholin-2- -yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[3-[(2-hydroxyacetyl)amino]- -4-methylphenyl]-3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-thiophen-3-ylpheny- l)-morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2- -yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[4-(hydroxymethyl)phenyl]-3- -oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1,3-dihydroind- ol-5-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-(4-iodophenyl)-3-oxomorphol- in-2-yl]-acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(4-cyclohexylphenyl)-3-oxomorpholin-2- -yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[2R)-3-oxo-4-(4-propan-2-ylphenyl)-- morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(4-ethylphenyl)-3-oxomorpholin-2-yl]-- 2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-(1H-indol-6-yl)-3-oxomorpho- lin-2-yl]-acetamide; (2R)--N-4-amidinophenyl)-2-[(2R)-4-(3,3-dimethyl-2-oxo-1H-indol-6-yl)-3-o- xomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-1,3-dihydroben- z-imidazol-5-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-p-tolylmethylmorpholi- n-2-yl]acetamide hydrochloric salt; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-thiophen-2-ylpheny- l)-morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-biphenyl-3-oxomorpholin-2-yl]-2-hydro- xy-acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(4'-tert-butylbiphenyl)-3-oxomorpholi- n-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(1H-pyrazol-4-yl)p- henyl]morpholin-2-yl]acetamide; (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]-N-(4-amidinopheny- l)-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-[4-(carbamylamino)phenyl]-3-oxomorpho- lin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[4-(methanesulfonamido)phen- yl]-3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(2-oxopyrrolidin-1- -yl)-phenyl]morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(3-oxomorpholin-4-- yl)-phenyl]morpholin-2-yl]acetamide; (2R)--N-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(2-oxo-1,3-oxazolidin- -3-yl)-phenyl]morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-[(2-phenylmethoxy-- acetyl)amino]phenyl]morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[4-[(2-hydroxyacetyl)amino]- phenyl]3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(3,3-dimethyl-2-oxo-1H-indol-5-yl)-3-- oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-(1H-indol-5-yl)-3-oxomorpho- lin-2-yl]-acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3H-1,3-benzoxa- zol-6-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-oxo-1,2-dihydroiso- indol-5-yl)morpholin-2-yl]acetamide; (2R)-2-[(2R)-4(4-Acetamidophenyl)-3-oxomorpholin-2-yl]-N-(1-aminoisoquino- lin-6-yl)-2-hydroxyacetamide; (2R)-2-[(2R)-4-(4-Acetamidophenyl)-3-oxomorpholin-2-yl]-2-hydroxy-N-(1-im- ino-2,3-dihydroisoindol-5-yl)acetamide; N-[4-[(2R)-2-[(1R)-2-(4-amidinoanilino)-1-hydroxy-2-oxoethyl]-3-oxomorpho- lin-4-yl]phenyl]propanamide; (2R)--N-(4-Amidinophenyl)-2-[(2R)-4-[4-[(2-cyclopropylacetyl)amino]phenyl- ]-3-oxomorpholin-2-yl]-2-hydroxyacetamide; N-[4-[(2R)-2-[(1R)-2-(4-Amidinoanilino)-1-hydroxy-2-oxoethyl]-3-oxomorpho- lin-4-yl]phenyl]cyclohexanecarboxamide; (2R)--N-(4-Amidinophenyl)-2-[(2R)-4-(4-aminophenyl)-3-oxomorpholin-2-yl]-- 2-hydroxyacetamide; (2R)--N-(4-Amidinophenyl)-2-[(2R)-4-(3-aminophenyl)-3-oxomorpholin-2-yl]-- 2-hydroxyacetamide; (2R)-2-[(2R)-4-(3-Acetamidophenyl)-3-oxomorpholin-2-yl]-N-(4-amidinopheny- l)-2-hydroxyacetamide; (2R)--N-(4-Amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[3-(2-oxopyrrolidin-1- -yl)phenyl]morpholin-2-yl]acetamide; (2R)--N-(4-Amidinophenyl)-2-[(2R)-4-[3-(carbamoylamino)phenyl]-3-oxomorph- olin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-Amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[3-(2-oxo-1,3-oxazoli- din-3-yl)phenyl]morpholin-2-yl]acetamide; (2R)--N-(4-Amidinophenyl)-2-hydroxy-2-[(2R)-4-[3-(methanesulfonamido)phen- yl]-3-oxomorpholin-2-yl]acetamide; (2R)-N-(4-Amidinophenyl)-2-hydroxy-2-[(2R)-4-[3-[(2-hydroxyacetyl)amino]p- henyl]-3-oxomorpholin-2-yl]acetamide; (2R)--N-4-Amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[3-(3-oxomorpholin-4-y- l)phenyl]morpholin-2-yl]acetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomor- pholin-2-yl]-2-hydroxyacetamide; (2R)-2-[(2R)-4(4-tert-Butylphenyl)-3-oxomorpholin-2-yl]-2-hydroxy-N-(1-im- ino-2,3-dihydroisoindol-5-yl)acetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(trifluoro- methyl)phenyl]morpholin-2-yl]acetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(trifluoro- methoxy)phenyl]morpholin-2-yl]acetamide; (2R)--N-(4-Amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[4-(trifluoromethoxy)- phenyl]morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-[4-(t- rifluoromethoxy)phenyl]morpholin-2-yl]acetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-[(2R)-4-(4-bromophenyl)-3-oxomorpholi- n-2-yl]-2-hydroxyacetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-[(2R)-4-(4-fluorophenyl)-3-Oxomorphol- in-2-yl]-2-hydroxyacetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-[(2R)-4-(4-chlorophenyl)-3-oxomorphol- in-2-yl]-2-hydroxyacetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-4-(4-isopropyloxyphen- yl)-3-oxomorpholin-2-yl]acetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-hydroxy-2-[(2R)-3-oxo-4-p-tolylmorpho- lin-2-yl]acetamide; (2R)--N-(1-Aminoisoquinolin-6-yl)-2-[(2R)-4-4-fluoro-o-tolyl)-3-oxomorpho- lin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-Amidinophenyl)-2-[(2R)-4(4-fluoro-o-tolyl)-3-oxomorpholin-2-yl- ]-2-hydroxyacetamide; (2R)--N-(4-Amidino-o-tolyl)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin- -2-yl]-2-hydroxyacetamide; (2R)--N-(4-Amidino-2-chlorophenyl)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomo- rpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-Amidino-2-fluorophenyl-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomor- pholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[3-(2-hydroxyethyl)phenyl]-- 3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-[5-trifluoromethyl)-2- -pyridyl]morpholin-2-yl]acetamide; (2R)-N-[4-amidinophenyl]-2-hydroxy-2-[2R)-4-[3-(methylsulfonyl)phenyl]-3-- oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[4-(2-methylsulfonylphenyl)- phenyl]-3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[2R)-4-[4-[2-(2-hydroxyethyl)phenyl- ]phenyl]-3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinphenyl)-2-hydroxy-2-[2R)-3-oxo-4-[3-(1H-pyrazol-4-yl)phe- nyl]morpholin-2-yl]acetamide; N-(4-amidinophenyl)-2-hydroxy-2-[4-(4-methylbenzoyl)morpholin-2-yl]acetam- ide; N-(4-amidinophenyl)-2-hydroxy-2-[4(p-tolylsulfonyl) morpholin-2-yl]acetamide; and N-(1-amino-6-isoquinolyl)-2-hydroxy-2-[4-(p-tolyl)morpholin-2-yl]acetamid- e ditrifluoroacetate; or a pharmaceutically acceptable salt thereof. 14. A compound of formula (I) of claim 1 consisting of: (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H- -quinolin-6-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-oxo-2,4-dihydro-1H- -isoquinolin-6-yl)morpholin-2-yl]acetamide; 2-[6-[(2R)-2-[(1R)-2-(4-amidinoanilino)-1-hydroxy-2-oxoethyl]-3-oxomorpho- lin-4-yl]-3-oxo-1,4-dihydroisoquinolin-2-yl]acetic acid; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-4-[2-(2-hydroxyethyl)-3-oxo-1- ,4-dihydroisoquinolin-6-yl]-3-oxomorpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-[2-(2-amino-2-oxoethyl)-3-oxo-1,4-dihyd- ro-isoquinolin-6-yl]-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3H-1,3-benzoxa- zol-5-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(1H-benzimidazol-5-yl)-3-oxomorpholin- -2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(2,2-dioxo-1,3-dihydro-2,1-benzothiaz- ol-5-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(2,2-dioxo-1,3-dihydro-2,1-benzothiaz- ol-6-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(3,3-dimethyl-2,2-dioxo-1H-2,1-benzot- hiazol-5-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(3,3-dimethyl-2,2-dioxo-1H-2,1-benzot- hiazol-6-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(2,2-oxo-3,4-dihydro-1H-benzo[d]thiaz- in-6-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(2,2-dioxo-3,4-dihydro-1H-benzo[d]thi- azin-7-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(1-oxo-2,3-dihydroiso- indol-5-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-oxo-2,4-dihydro-1H- -isoquinolin-7-yl)morpholin-2-yl]acetamide; (2R)--N-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-oxo-3,4-dihydro-1H-qu- inolin-7-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4(2,2-dioxo-3,4-dihydro-1H-benzo[c][1,2- ,6]-thiadiazin-6-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(4-amidinophenyl)-2-[(2R)-4-(2,2-dioxo-3,4-dihydro-1H-benzo[c][1,- 2,6]-thiadiazin-7-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)-2-[(2R)-4-(3,3-dimethyl-2-oxo-1H-indol-5-yl)-3-oxomorpholin-2-yl]-2-- hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomorpholin-2-yl]-2-hydroxy-N-(1-i- mino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(4-acetamidophenyl)-3-oxomorpholin-2-yl]-2-hydroxy-N-(1-im- ino-2,3-dihydroisoindol-5-yl)acetamide; (2R)--N-(1-aminoisoquinolin-6-yl)-2-[(2R)-4-(3,3-dimethyl-2-oxo-1H-indol-- 5-yl)-3-oxomorpholin-2-yl]-2-hydroxyacetamide; (2R)--N-(1-aminoisoquinolin-6-yl)-2-[(2R)-4-(4-tert-butylphenyl)-3-oxomor- pholin-2-yl]-2-hydroxyacetamide; and (2R)-2-[(2R)-4(4-acetamidophenyl)-3-oxomorpholin-2-yl]-N-(1-aminoisoquino- lin-6-yl)-2-hydroxyacetamide; or a pharmaceutically acceptable salt or solvate thereof. 15. A compound of formula (I) of claim 1 selected from the group consisting of: (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-oxo-2-propylis- oindolin-5-yl)morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-oxo-2-(2,2,2-t- rifluoroethyl)isoindolin-5-yl)morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-oxoisoindol- in-5-yl)-3-oxomorpholin-2-yl)acetamide; (R)--N-(4-(aminomethyl)phenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-oxoisoindol- in-5-yl)-3-oxomorpholin-2-yl)acetamide; (R)-2-hydroxy-2-((R)-4-(2-methyl-3-oxoisoindolin-5-yl)-3-oxomorpholin-2-y- l)-N-(1,2,3,4-tetrahydroisoquinolin-6-yl)acetamide; (R)-2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3-oxomorpholin-2-yl)-N-(4-c- arbamimidoylphenyl)-2-hydroxyacetamide; (R)-2-((R)-4-(3,5-bis(trifluoromethyl)phenyl)-3-oxomorpholin-2-yl)-2-hydr- oxy-N-(1-oxoisoindolin-5-yl)acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(4,4-difluoropiper- idin-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(pyrrolidin-1-ylsu- lfonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(methylsulfonyl)ph- enyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-phenylphenyl)morph- olin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(pyrrolidin-1-ylca- rbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(morpholin-4-ylcar- bonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(4,4-difluoropiper- idin-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(1,2,3,4-tetrahydr- oisoquinolin-2-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(isoindolin-2-ylca- rbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-aminophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(morpholin-4-ylcarbo- nyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(pyrrolidin-1-ylca- rbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-fluorophenyl)morph- olin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3,5-difluorophenyl)m- orpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(pyrrolidin-1-ylsu- lfonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(4-methylsulfonylp- iperazin-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2-fluoropyridin-5-yl- )morpholin-2-yl]acetamide; (R)--N-(3-aminobenzo[d]isoxazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(4-(triflu- oromethyl)phenyl)morpholin-2-yl)acetamide; (R)--N-(3-amino-1H-indazol-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(4-(trifluorome- thyl)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(4-(trif- luoromethyl)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-{(R)-3-oxo-4-[4-(trifluorometh- yl)phenyl]morpholin-2-yl}acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluorometh- yl)phenyl)morpholin-2-yl)acetamide; N-(4-amino-7-quinazolinyl)-alpha(R)-hydroxy-3-oxo-4-[4-(trifluormethyl)ph- enyl]-2(R)-morpholineacetamide; N-[4-(aminomethyl)phenyl]-alpha(R)-hydroxy-3-oxo-4-[4-(trifluoromethyl)ph- enyl]-2(R)-morpholineacetamide; N-[4-(aminoiminomethyl)phenyl]-4-[3-(aminomethyl)phenyl]-alpha(R)-hydroxy- -3-oxo-2(R)-morpholineacetamide; and N-[4-(aminocarbonyl)phenyl]-alpha(R)-hydroxy-3-oxo-4-[4-(trifluoromethyl)- phenyl]-2(R)-morpholineacetamide; (R)--N-(4-Carbamimidoylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(trifluorometh- oxy)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-Carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-oxoisoindol- in-5-yl)-3-oxomorpholin-2-yl)acetamide; (R)--N-(4-(Aminomethyl)phenyl)-2-hydroxy-2-((R)-4-(2-methyl-1-oxoisoindol- in-5-yl)-3-oxomorpholin-2-yl)acetamide; (R) --N(Aminomethyl)phenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholino)phen- yl)morpholin-2-yl)acetamide; (R)--N-(1-Aminoisoquinolin-6-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpho- lino)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-Carbamimidoyl-3-chlorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-ox- omorpholino)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-Carbamimidoyl-3-methylphenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-ox- omorpholino)phenyl)morpholin-2-yl)acetamide; (R)-2-Hydroxy-2-((R)-3-oxo-4-(3-(3-oxomorpholino)phenyl)morpholin-2-yl)-N- -(1,2,3,4-tetrahydroisoquinolin-6-yl)acetamide; 2-(3-((R)-2-((R)-2-(4-Carbamimidoylphenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)phenoxy)acetic acid; Ethyl 2-(3-((R)-2-((R)-2-(4-(aminomethyl)phenylamino)-1-hydroxy-2-oxoethyl)-3-o- xomorpholino)phenoxy)acetate; (R)--N-(4-carbamimidoyl-2-ethylphenyl)-2-hydroxy-2-((R)-4-(2-methyl-3-oxo- isoindolin-5-yl)-3-oxomorpholin-2-yl)acetamide; (R)-2-Hydroxy-N-(2-methyl-1H-indol-5-yl)-2-((R)-3-oxo-4-(3-(3-oxomorpholi- no)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-methoxyphenyl)-3-oxo- morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-fluorophenyl)-3-oxom- orpholin-2-yl)acetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-(difluoromethoxy)phe- nyl)-3-oxomorpholin-2-yl)acetamide; (R)--N-(6-carbamimidoylpyridin-3-yl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-oxomo- rpholino)phenyl)morpholin-2-yl)acetamide; N-[4-(aminoiminomethyl)phenyl]--[3-(1,1-dioxido-2-isoizolidinyl)phenyl]-a- lpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide; (R)--N-(4-carbamimidoylphenyl)-2-((R)-4-(4-fluoro-2-methoxyphenyl)-3-oxom- orpholin-2-yl)-2-hydroxyacetamide; (R)--N-(4-carbamimidoylphenyl)-2-hydroxy-2-((R)-4-(2-isopropoxyphenyl)-3-- oxomorpholin-2-yl)acetamide; (R)-2-((R)-4-(2-(2-amino-2-oxoethoxy)phenyl)-3-oxomorpholin-2-yl)-N-(4-ca- rbamimidoylphenyl)-2-hydroxyacetamide; (R)--N-(4-carbamimidoyl-3-fluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(3-ox- omorpholino)phenyl)morpholin-2-yl)acetamide; (R)--N-(4-carbamimidoyl-3,5-difluorophenyl)-2-hydroxy-2-((R)-3-oxo-4-(3-(- 3-oxomorpholino)phenyl)morpholin-2-yl)acetamide; 3-((R)-2-((R)-2-(4-carbamimidoyl-3-fluorophenylamino)-1-hydroxy-2-oxoethy- l)-3-oxomorpholino)benzoic acid; N-(2,3-Dihydro-1-iminio-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-- oxo-4-morpholinyl)phenyl]-2(R)-morpholineacetamide; 4-(3-Cyanophenyl)-N-(2,3-dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydro- xy-3-oxo-2(R)-morpholineacetamide; N-(2,3-Dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[4-(1-p- yrrolidinylcarbonyl)phenyl]-2(R)-morpholineacetamide; N-(2,3-Dihydro-1-imino-1H-isoindol-5-yl)-4-[3-[(dimethylamino)carbonyl]ph- enyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide; n-(2,3-Dihydro-1-imino-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(1-p- yrrolidinylcarbonyl)phenyl]-2(R)-morpholineacetamide; N-(2,3-Dihydro-1-imino-1H-isoindol-5-yl)-4-[4[(dimethylamino)carbonyl]phe- nyl]-alpha(R)-hydroxy-3-oxo-2(R)-morpholineacetamide; N-[4-(Aminoiminomethyl)phenyl]-alpha(R)-hydroxy-3-oxo-4-[3-(1 h-tetrazol-5-yl)phenyl]-2(R)-morpholineacetamide; N-(2,3-dihydro-1H-isoindol-5-yl)-alpha(R)-hydroxy-3-oxo-4-[3-(3-oxo-4-mor- pholinyl)phenyl]-2(R)-morpholineacetamide; [4-[2(R)-[2-[[4-(Aminoiminomethyl)phenyl]amino]-1(R)-hydroxy-2-oxoethyl]-- 3-oxo-4-morpholinyl]phenyl]pentafluorosulfur, [3-[2(R)-[2-[[4-(Aminoiminomethyl)phenyl]amino]-1(R)-hydroxy-2-oxoethyl]-- 3-oxo-4-morpholinyl]phenyl]pentafluorosulfur, (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[2R)-3-oxo-4-(4-(1,1-dioxothiomorph- olin-4-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(dimethylaminocarb- onyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(dimethylamino)sul- fonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(dimethylaminocarbony- l)phenyl)morpholin-2-yl]acetamide; (2R)--N-amidinophenyl-2-hydroxy-2-[(2R)-3-oxo-4-(4-fluoro-3-(morpholin-4-- ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-(dimethyl-D.sub.6-- aminocarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(dimethyl-D.sub.6-- aminocarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(dimethylaminocarb- onyl) 4-fluorophenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo 4-(4-methoxy-D.sub.3-phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-methoxy-D.sub.3-ph- enyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-fluoro-3-(pyrrolid- in-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(dimethylaminocarb- onyl)-4-methylphenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-methyl-3-(morpholi- n-4-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-methyl-3-(pyrrolid- in-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-fluoro-5-(pyrrolid- in-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-fluor O-5-(morpholin-4-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(dimethylaminocarb- onyl)-5-fluorophenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[2R)-3-oxo-(3-(dimethylaminocarbony- l)-2-methylphenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(piperidin-1-ylcar- bonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(azetidin-1-ylcarbon- yl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-((2R,5R)-(-)-trans- -dimethylpyrrolidin-1-ylcarbonyl)phenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-fluorophenyl)morph- olin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3,4,5-trifluoropheny- l)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3,4-difluorophenyl)m- orpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(2,4-difluoropyridin-- 3-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4,5-difluoropyridin-- 3-yl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-carboxyphenyl)morp- holin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(carboxymethyl)met- hyl)carbamoylphenyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-carboxyphenyl)morp- holin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(4-methoxycarbonylphe- nyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-methoxycarbonylphe- nyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-carboxy-4-fluoroph- enyl)morpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-(methoxycarbonylme- thyl)methyl)carbamoylphenyl)morpholin-2-yl]acetamide; (2R)--N-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-carboxymethylphenyl)m- orpholin-2-yl]acetamide; (2R)--N-(4-amidinophenyl)-2-hydroxy-2-[(2R)-3-oxo-4-(3-carboxy-5-fluoroph- enyl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2-dihydroisoindol-5-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2-dihydroisoindol-6-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2,3,4-tetrahydroisoquinolin-6-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2,3,4-tetrahydroisoquinolin-7-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-1,2,3,4-tetrahydroquinolin-6-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(2-methyl-3- -oxo-1,2-dihydroisoindol-5-yl)-3-oxo-morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-2-(2,2,2-trifluoroethyl)-1,2-dihydroisoindol-5-yl)morpholin-2-yl]acetami- de; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3- -oxo-2-propyl-1,2-dihydroisoindol-5-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-4-(2-methyl-3- -oxo-1,2-dihydroisoindol-6-yl)-3-oxo-morpholin-2-yl]acetamide; (2R)-2-[(2R)-4(2-(Difluoromethoxy)phenyl)-3-oxo-morpholin-2-yl]-2-hydroxy- -N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(2-Fluorophenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-imin- o-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(4-Fluorophenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-imin- o-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(3-Fluorophenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-imin- o-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(3,4-Difluorophenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-- imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(3,5-Difluorophenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-- imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3,4,- 5-trifluorophenyl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(4-tr- ifluoromethylphenyl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-tr- ifluoromethylphenyl)morpholin-2-yl]acetamide; (2R)-2-[(2R)-4-(4-Fluoro-3-(morpholin-4-ylcarbonyl)phenyl)-3-oxo-morpholi- n-2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4(3-Dimethylaminocarbonyl)-4-fluorophenyl)-3-oxo-morpholin-2- -yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(4-Fluoro-3-(pyrrolidin-1-ylcarbonyl)phenyl)-3-oxo-morphol- in-2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(3-(Dimethylaminocarbonyl)-5-fluorophenyl)-3-oxo-morpholin- -2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(5-Fluoro-3-(pyrrolidin-1-ylcarbonyl)phenyl)-3-oxo-morphol- in-2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(5-Fluoro-3-(morpholin-4-ylcarbonyl)phenyl)-3-oxo-morpholi- n-2-yl]-2-hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)acetamide; (2R)-2-[(2R)-4-(3-Carboxyphenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-imi- no-2,3-dihydroisoindol-5-yl)acetamide; and (2R)-2-[(2R)-4-(4-Chlorophenyl)-3-oxo-morpholin-2-yl]-2-hydroxy-N-(1-imin- o-2,3-dihydroisoindol-5-yl)acetamide; or a pharmaceutically acceptable salt or solvate thereof. 16. A compound of formula (I) of claim 1 consisting of: (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2-dihydroisoindol-5-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2-dihydroisoindol-6-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(3-ox- o-1,2,3,4-tetrahydroisoquinolin-6-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imin-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4(3-oxo-- 1,2,3,4-tetrahydroisoquinolin-7-yl)morpholin-2-yl]acetamide; (2R)-2-Hydroxy-N-(1-imino-2,3-dihydroisoindol-5-yl)-2-[(2R)-3-oxo-4-(2-ox- o-1,2,3,4-tetrahydroquinolin-6-yl)morpholin-2-yl]acetamide; or a pharmaceutically acceptable salt or solvate thereof. 17. A pharmaceutical composition comprising at least one compound of claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable carrier. 18. A pharmaceutical composition comprising: a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of at least one agent selected from the group consisting of: (a) anticoagulants, (b) anti-thrombin agents, (c) anti-platelet agents, (d) fibrinolytic, (e) hypolipidemic agents, (f) antihypertensive agents, and (g) anti-ischemic agents. 19. A pharmaceutical composition comprising: a therapeutically effective amount of at least one compound of claim 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, and an effective amount of at least one agent selected from the group consisting of (a-1) warfarin, (a-2) heparin, (a-3) aprotinin, (a-4) synthetic pentasaccharide, (a-5) direct acting thrombin inhibitors including hirudin and argatroban, (a-6) a factor VIIa inhibitor, (a-7) a factor VIIIa inhibitor, (a-8) a factor IXa inhibitor different from the compounds of Formula (I), (a-9) a factor Xa inhibitor, (a-10) a factor XIa inhibitor, (a-11) a thrombin inhibitor, (a-12) a TAFI, (a-13) a fibrinogen inhibitor, (b-1) a boroarginine derivative, (b-2) a boropeptide, (b-3) heparin, (b-4) hirudin, (b-5) argatroban, (c-1) a NSAID, (c-2) a IIb/IIIa antagonist, (c-3) a thromboxane-A2-receptor antagonist, (c-4) a thromboxane-A2-synthetase inhibitor, (c-5) a PDE-III inhibitor, (c-6) a PDE V inhibitor, (c-7) a ADP receptor antagonist, (c-8) an antagonist of the purinergic receptor P2Y1, (c-9) an antagonist of the purinergic receptor P2Y12, (d-1) tissue plasminogen activator (TPA, natural or recombinant) and modified forms thereof; (d-2) anistreplase, (d-3) urokinase, (d-4) streptokinase, (d-5) tenecteplase (TNK), (d-6) lanoteplase (nPA), (d-7) a factor VIIa inhibitor, (d-8) a PAI-I inhibitor, (d-9) an alpha-2-antiplasmin inhibitor, (d-10) an anisoylated plasminogen streptokinase activator complex, (e-1) a HMG-CoA reductase inhibitor, (e-2) a squalene synthetase inhibitor, (e-3) a fibrate, (e-4) a bile acid sequestrant, (e-5) an ACAT inhibitor, (e-6) a MTP inhibitor, (e-7) a lipooxygenase inhibitor, (e-8) a cholesterol absorption inhibitor, (e-9) a cholesterol ester transfer protein inhibitor, (f-1) an alpha adrenergic blocker, (f-2) a beta adrenergic blocker, (f-3) a calcium channel blocker, (f-4) a diuretics, (f-5) a rennin inhibitor, (f-6) an angiotensin-converting enzyme inhibitor, (f-7) an angiotensin-II-receptor antagonist, (f-8) an ET receptor antagonist, (f-9) a Dual ET/All antagonist, (f-10) a neutral endopeptidase inhibitors, (f-11) a vasopepsidase inhibitor, (g-1) a Class I agent, (g-2) a Class II agent, (g-3) a Class III agent, a (g-4) Class IV agent, (g-5) a K+ cannel opener, (g-6) an IKur inhibitor and (g-7) a cardiac glycoside.

Details for Patent 8,642,582

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Bayer Healthcare Pharmaceuticals Inc.	TRASYLOL	aprotinin	Injection	020304	12/29/1993		2039-02-26
Microbix Biosystems Inc.	KINLYTIC	urokinase	For Injection	021846	01/16/1978		2039-02-26
Genentech, Inc.	TNKASE	tenecteplase	For Injection	103909	06/02/2000		2039-02-26